Memory CD8 T cells are important for protection against many viral infections. Our understanding of memory CD8 T cells now includes an appreciation for the heterogeneity that exists within the memory CD8 T cell population including lymph node homing "central" memory CD8 T cells (TCM) and tissue homing "effector" memory T cells (TEM). While the precise definitions of these subsets are varied, it is not clear which subpopulation(s) of memory CD8 T cells will protect most efficiently from pathogenic influenza virus infection. Some studies indicate that TCM provide better protective immunity against other viral infections compared to TEM while circumstantial evidence from models of respiratory viral infections suggests that lung resident memory CD8 T cells may be important. The overall goal of the current application is to examine the role of different memory CD8 T cell populations in protective immunity to influenza virus infection. Specifically, we hypothesize that different memory CD8 T cell subpopulations will cooperate to confer optimal protective immunity and that a unique aspect of this cooperation is rapid production of chemokines (including Rantes, Mip1a and Mip1[unreadable]) by tissue homing TEM that is crucial for rapidly recruiting systemic TCM and other antiviral cells. We will test this hypothesis during influenza virus infection by examining the protective capacity of memory CD8 T cell subsets defined two ways, by determining whether optimal protective immunity is achieved with both TCM and TEM subsets present compared to either subset alone, and by defining the functional properties of these subsets including in vitro and in vivo production of Rantes, Mip1a and Mip1[unreadable]. In addition, we will determine how the absence of Rantes in different memory CD8 T cell subpopulations influences protective immunity (or immunopathology). The studies proposed in this application will help define the protective capacity of memory CD8 T cell subsets alone and together during influenza virus infection. These studies will also begin to define the mechanisms of protection of different memory CD8 T cell subpopulations and will likely provide important insights into the type of immunity that should be targeted by vaccine efforts aimed at inducing heterosubtypic T cell immunity to influenza virus. [unreadable] [unreadable] [unreadable]